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Life Extension Magazine

LE Magazine May 2004
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Histone Deacetylase Inhibitors
New Anticancer Treatment Excites Researchers
By Terri Mitchell

The use of “histone deacetylase inhibitors” forms the basis for a sophisticated new anticancer treatment being developed at the National Cancer Institute. The treatment is founded on the idea that the abnormal behavior of cancer cells can be targeted and reversed.

Deacetylase inhibitors go straight to the source of cancer cell behavior: DNA. The inhibitors do not add or delete DNA, but instead normalize existing DNA, forcing the cells to behave normally.1,2 After treatment, cancer cells either self-destruct or revert to normal growth. Because the inhibitors seem to target cancer cells and work through normal cellular channels rather create generalized toxicity, they appear to be more “natural” than standard chemotherapy. Although the drugs have been tried in comparatively few people, the results to date have been dramatic.

One subject who responded, a man with peripheral T-cell lymphoma, had been treated with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin. When recruited into a study at the National Cancer Institute, he had lumps all over his body, with red splotches on his skin, enlarged lymph nodes, and a mass on his foot. After receiving a histone deacetylase inhibitor known as FK228 (formerly FR901228), his symptoms disappeared and he went into remission. Eighteen months later, he is still well. Another man with cutaneous T-cell lymphoma was covered in hundreds of purple tumors when he received FK228. After treatment, almost all of the tumors disappeared.3

Currently, a phase II trial is under way with 40 more T-cell lymphoma patients. The inhibitor also is being used against thyroid, lung, prostate, leukemia, and other cancers. Dr. Susan Bates of the National Cancer Institute is hoping that FK228 may activate genes in cancer cells that allow radioactive iodine to enter the cells, which could be useful in treating breast and thyroid cancer. According to Dr. Bates, FK228 is much more powerful than butyrate, a natural histone deacetylase inhibitor. FK228 is a copy of a peptide originally isolated from a soil bacterium.

Another cancer treatment that is being explored is combination therapy in conjunction with a methylation enzyme (methyltransferase) inhibitor. Methylase enzyme inhibitors are similar to deacetylase inhibitors in that both are avenues for controlling the genes of cancer cells. The two processes are interrelated, so drugs targeting both are being tried in combination.

To date, FK228 has not been used in combination with conventional chemotherapy, but as soon as the National Cancer Institute is convinced that the drug works on its own without undue toxicity, the two will be tried together. Dr. Bates is hoping deacetylase inhibitors will attack the problem of recurrence and drug resistance.

Histone deacetylase inhibitors and drugs that affect methylation represent a treatment approach that goes to the very essence of what cancer is: good cells gone bad.4 That cancer genes can be made “normal” again with these types of drugs already has been proven. These new drugs may foretell a brave new world of cancer therapy that is more reality than hype.

More information about lymphoma treatment with the FK228 histone deacetylase inhibitor is available through the National Cancer Institute by calling Robin Frye, RN, at (301) 402-5958. The treatment is available at many US cancer centers. More information about treating thyroid cancer with histone deacetylase inhibitors is available by calling Deborah Draper, RN, BSN, at (301) 435-8525. For more information about other cancers being treated with the new therapy, visit the National Cancer Institute website (http://cancer.gov/clinicaltrials).


enlarge photo

Clinical effects of depsipeptide. Photographs of patient 3 (panel A) and photographs and abdominal CT sections of patient 4 (panel B) before (left) and after (right) treatment with depsipeptide. These demonstrate a response of the cutaneous tumors on the face and torso of patient 3 and of the erythematous plaques on the legs and retroperitoneal lymphadenopathy of patient 4 after treatment with depsipeptide.*

* Piekarz RL. Inhibitor of histone deacetylation, depsipeptide (FR901228) in the treatment of periphal and cutaneous T-cell lymphoma. Blood. 2001; 98(9):2865-68. Used with permission.

References

1. Kitazono M, Bates S, Fok P, Fojo T Blagosklonny MV. The histone deacetylase inhibitor FR901228 (desipeptide) restores expression and function of pseudo-null p53. Cancer Biol Ther. 2002 Nov-Dec;1(6):665-8.

2. Primeau M, Gagnon J, Momparler RL. Synergistic antineoplastic action of DNA methylation inhibitor 5-AZA-2'-deoxycytidine and histone deacetylase inhibitor dep- sipeptide on human breast carcinoma cells. Int J Cancer. 2003 Jan 10;103(2):177-84.

3. Piekarz RL, Robey R, Sandor V, et al.Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood. 2001 Nov 1;98(9):2865-8.

4. Imhof A, Wolffe AP. Transcription: gene control by targeted histone acetylation. Curr Biol. 1998 Jun 4;8(12):R422-4.

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